Solid organ transplantation is a highly successful form of intervention following irreversible organ failure, with approximately 35,000 transplants performed annually in the US. Adequate suppression of the immune system is required for graft survival, and once- or twice-daily immunosuppressive therapy with the calcineurin inhibitor tacrolimus is central to allograft rejection prevention. Immunosuppression with tacrolimus presents significant pharmaceutical challenges, including highly variable pharmacokinetics and a narrow therapeutic index, where once- or twice-daily administration results in peaks in blood concentration which contribute to toxicity and troughs which can lead to graft rejection. In addition, while adherence to immunosuppressive therapy is critical to graft survival, non-adherence rates among transplant recipients are high, averaging about 23% across all solid organ transplant types, with highest rates (36%) observed for kidney transplants. Non-adherence is most problematic during adolescence and young adulthood, which is also the time of maximal immune system activity and biological risk for organ rejection. Lyndra has developed a novel oral drug delivery technology that provides extended therapeutic drug levels with infrequent dosing. The technology is based on a gastric residence dosage form that delivers drug continuously to the stomach and then exits the body through the lower GI tract. Lyndra dosage forms have been manufactured under cGMP and are currently in multiple clinical trials. Studies in large animals demonstrate continuous drug release and gastric retention for one week or more. Human clinical data from multiple studies show an excellent safety profile and sustained drug delivery. The proposed research is a collaboration between Lyndra and the NYU Langone Transplant Institute. Our goal is to develop a once-weekly oral tacrolimus-prednisone fixed-dose combination for maintenance therapy in kidney transplant recipients previously stabilized on daily therapy. Once-weekly tacrolimus-prednisone may benefit patients by (1) providing a safer, more effective therapy by maintaining trough tacrolimus concentrations within the therapeutic range with reduced peak-trough variation, (2) reducing total dose and side effects, and (3) substantially improving adherence to long-term maintenance immunosuppressive therapy. Lyndra has established technical feasibility of this concept by demonstrating tacrolimus and prednisone encapsulation, stability and controlled release under simulated gastric conditions. The objective of this Direct-to-Phase II SBIR proposal is to develop and manufacture a tacrolimus-prednisone dosage form for a Phase 1 clinical trial and to lay the clinical and regulatory groundwork for development of the product. The proposed work includes IND-enabling pharmaceutical development and GMP manufacturing of clinical supplies along with regulatory and clinical planning activities that culminate in the submission of an IND to the US FDA for a first-in-human clinical trial. Lyndra Inc Confidential Page 1